Targeting RSK for Treatment of Pediatric Acute Myeloid Leukemia
Abstract
Acute leukemia is the most common type of childhood cancer. The overall survival of children with acute myeloid leukemia (AML) is 60% and the treatment is intensive chemotherapy or stem cell transplantation, which is associated with significant toxicity and long-term side effects. There are very few available therapies for children with AML who relapse. Therefore, it is critical to find new treatment approaches to treat pediatric AML. The area of focus for this research in the Rare Cancer Research Program is THERAPY: Identify Novel therapeutic strategies, including drug repurposing. We previously found that a protein known as CREB is overproduced in AML cells and is associated with a worse prognosis. CREB increases genes that cause cell growth and leukemia progression. We knocked down CREB in AML cells, which decreased AML cell growth but did not affect normal blood forming cells. Our laboratory showed that a small molecule that inhibits CREB results in decreased AML cell growth and progression in animal models. However, this small molecule is not ready for clinical application. CREB is activated by a protein known as RSK (ribosomal S6 Kinase). There are several small molecules targeting RSK that are currently in clinical trials for adult solid tumors. We have preliminary data that two RSK inhibitors inhibit the growth of AML cells without toxicity to normal cells. In this application, we propose to study the effects of combinations of RSK and chemotherapy in AML cells and in animal models of pediatric AML. We also propose to study the signals within AML cells treated with RSK inhibitors to identify potential biomarkers to predict response in AML patients. Therefore, preclinical results from our studies will potentially result in a phase 1 clinical trial for relapsed/refractory pediatric AML. The type of patients this research will help is children with relapsed or refractory AML for which there is no other therapy. As for the projected time anticipated to achieve a clinically relevant outcome, we anticipate that by the end of the funding period we will have the preclinical data to write a phase 1 clinical trial for relapsed/refractory pediatric AML. Looking at potential clinical applications, benefits, and risks: based on our preclinical data, we anticipate that our research will provide an effective, less toxic alternative to intensive chemotherapy and potentially stem cell transplantation. Regarding likely contributions of the study to contribute to advancing rare cancer research, the overall goal of this research is to develop new approaches to treat pediatric AML and improve the survival and quality of life of children with this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311008
Entities
People
- Kathleen Sakamoto
Organizations
- Stanford University
- United States Army